The present invention relates to a method of alleviating the accumulation of waste nitrogen in human beings.
In a healthy person, the potentially toxic nitrogenous compounds which accumulate as the body degrades proteins are synthesized into urea which is rapidly excreted into the urine. However, for those who suffer kidney failure, liver failure or inborn errors of urea synthesis this pathway is defective. The accumulation of nitrogenous compounds resulting from such a blockage leads to considerable morbidity and mortality.
In the case of an inborn error of urea synthesis, the major metabolic abnormality is the inability of the body to convert waste nitrogen into urea. As a consequence, various nitrogenous metabolites accumulate in the body, the most toxic being ammonium although other materials, such as glutamine, glutamate and alanine, also increase.
Previous therapeutic approaches for treating patients with urea cycle enzymopathies (as well as other nitrogen accumulation diseases cited earlier) have been designed to reduce the requirement for urea synthesis by quantitative and qualitative manipulation of dietary protein, amino acids and/or their nitrogen free analogues. Generally speaking, however, the mortality of inborn errors of the urea-cycle remained high and success was measured in terms of increased survival time. Thus, for example, even with the above-cited therapeutic approaches children with the neonatal form of these diseases rarely survived past one year of age.
A more recent approach to remedy this pervasive problem is described in U.S. Pat. No. 4,284,647 where benzoic acid, phenylacetic acid, or the salts thereof convert the waste nitrogen into amino acid acylation products which the body can successfully excrete as urinary nitrogen. More specifically, that patent teaches that phenylacetate reacts with the nitrogen to form phenylacetylglutamine which is subsequently excreted by the body. Since such a reaction is in no way dependent on the urea synthesis or excretion, it is an effective treatment from those suffering from nitrogen accumulation diseases. See also "Treatment of Inborn Errors of Urea Synthesis," New England Journal of Medicine, 306; 1387-1392 (1982).
It is well known that there is considerable species specificity in the amino acid that conjugates with phenylacetate. (James M. D., Smith, R. L., Williams, R. T., and Reidenberg, M., "The Conjugation of Phenylacetic Acid in Man, Sub-human Primates and Some Non-primate Species," Proc. R. Soc. Lond. B. 182: 25-35, 1972; Power, F. S., Detoxification of Phenylacetic Acid by the Chimpanzee. Proc. Soc. Exptl. Biol. Med 33: 598, 1935). Only man, the baboon and the chimpanzee completely or nearly completely conjugate phenylacetate with glutamine whereas other species conjugate it with glycine (as in the dog), taurine, ornithine or glucuronic acid.
Despite the effectiveness of the phenylacetate treatment, specific drawbacks have been encountered in its use. The compound, which is generally administered to patients orally, has a vile and pervasive odor which renders it virtually unpalatable. Thus, patients fail to comply with the prescribed treatment due to their reluctance to subject themmselves to this odor, and this reluctance can be a serious problem in successful therapy. Another disadvantage of the phenylacetate results from the division of the daily dosage. After administering the compound, the waste nitrogen present in the patient quickly reacts to form the amino acid acylation product and plasma levels of phenylacetate fall to nearly zero in six hours. At this point no further amino acid acetylation can occur unless another dose of phenylacetate is given.
Phenylbutyrate in all mammals including man is metabolized to phenylacetate by the fatty acid beta-oxidation mechanism because the side chain is even numbered. (Lehninger, A., Biochemistry, Worth Publishers, N.Y., (1976.)